Bowels are organs which digest and absorb nutrients and water essential for activities of life of organisms. Meanwhile, they are also organs which have an immunodefense performance for excluding foreign matters such as pathogens and keep life conservation by controlling contradictory qualities in a well-balanced manner. It is however known that when the balance of these functions becomes abnormal, this dynamic equilibrium is broken to induce various bowel diseases. Especially, inflammatory bowel diseases (abbreviated as IBD), of which patients have been increased in number in recent years, are associated with abnormalities in digestive organs such as abdominal pain, diarrhea, mucous and bloody stool and the like and, in view of pathogenic states thereof, grouped into ulcerative colitis and Crohn's disease.
Ulcerative colitis is a disease mainly showing diffuse bowel mucosal inflammation restricted to the large intestine, where repeated inflammation leads to the onset of colorectal cancer, surgery is often necessary, and postoperative problems of increased frequency of defecation, stool leakage and onset of pouchitis are caused. Crohn's disease is a disease showing lesion spreading from the small intestine to the large intestine, and intense, discontinuous all layer inflammation starting from the submucosal layer, where repeated inflammation leads to the intestinal complications (stenosis, fistula, abscess) that require operation (Inflamm. Bowel. Dis., 8, 244-250, 2002).
In recent years, it has been known that an anti-TNF-α antibody is effective as a therapeutic agent of Crohn's disease and ulcerative colitis (N. Engl. J. Med., 353, 2462-2476, 2005). Also, an anti-α4 integrin antibody Natalizumab has been reported to be effective as a therapeutic agent of Crohn's disease (J. Clin. Invest., 118, 825-826, 2008). Nevertheless, in the current therapies including the antibodies, 40-60% of IBD patients has not yet received a satisfactory medical treatment. Accordingly, the development of an effective therapeutic agent has been in high demand in a medical care (J. Clin. Gastroenterol., 41, 799-809, 2007).
CD81 is a cell surface molecule of 26 kDa, which is expressed in wide-ranging cells. It has an activity of decreasing a threshold of B cell activation by forming a complex with CD21, CD19 and Leu 13 in a B cell. In a T cell, it is associated with CD4 and CD8 to transduce stimulatory signal into cells. In view of these matters, CD81 is considered to have a significant role in an immune response to a heterologous antigen. Moreover, it is involved in various integrins physiologically and functionally to activate VLA-4 (α4β1 integrin) in a B cell or LFA-1 (αLβ2 integrin) in a thymocyte.
As a disease associated with CD81, hepatitis C is known (Science, 282, 938-941, 1998).
In recent years, it has been reported that anti-CD81 antibody is useful for the treatment of IBD (WO 2005/021792). IBD associated with T cell migration (J. Clin. Invest., 118, 825-826, 2008; Inflamm. Bowel Dis., 16(4), 583-92, 2010; J. Pharmacol. Exp. Ther., 327(2), 383-92, 2008). As other diseases associated with T cell migration, multiple sclerosis and psoriasis are known (J. Clin. Invest., 118, 825-826, 2008; J. Neuroimmunol., 60, 17-28, 1995; Expert Opinion on Biological Therapy, 3(2), 361-70, 2003).
To be specific, it has been reported that bowel mucosa layer T cells or peripheral blood T cells of a patient suffering from IBD such as Crohn's disease or ulcerative colitis highly express a chemokine receptor CXCR4 and exhibit a strong chemotactic response to a chemokine CXCL12 (Inflamm. Bowel Dis., 16(4), 583-92, 2010), and that colitis is cured by administering a CXCR4 inhibitor to an IBD model, dextran sulfate-induced mouse colitis model (J. Pharmacol. Exp. Ther., 327(2), 383-92, 2008), and that an anti-α4 integrin antibody Natalizumab, which treats IBD by suppressing T cell migration, has been approved as a pharmaceutical product (J. Clin. Invest., 118, 825-826, 2008).
It has also been reported that T cell migration is important for the pathology of an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) mouse (J. Neuroimmunol., 60, 17-28, 1995). Natalizumab is thought to exert its therapeutic efficacy by blocking the α4 integrin-mediated adhesion of circulating T cells to the blood-brain barrier in EAE mice (J. Clin. Invest., 118, 825-826, 2008). Natalizumab is also effective for the treatment of multiple sclerosis.
Furthermore, it has been reported that T cells abundantly accumulate in psoriatic skin and that an anti-LFA-1 antibody Efalizumab (trade name: Raptiva), which suppresses T cell migration, is effective for the treatment of psoriasis (Expert Opinion on Biological Therapy, 3(2), 361-70, 2003).
There arise various problems based on the species difference when clinical application of an anti-CD81 antibody to human is desired. For example, administration of a mouse antibody to human may be limited by short serum half-life, failure to trigger certain kinds of human effector function and induction of undesirable human immune response to the mouse antibody (“human anti-mouse antibody” (HAMA) reaction) (Blood, 62, 988-995, 1983; Cancer Res., 45, 879-885, 1985). Moreover, even an anti-TNFα antibody (Remicade), which is a chimeric molecule obtained by binding the variable (V) region of a rodent antibody with the constant (C) region of a human antibody, may induce a human anti-chimeric antibody (HACA) and cause an infusion reaction or loss of drug efficacy (Current Gastroenterology Reports, 5(6), 501-5, 2003).